DC-specific Caspase-8 Deletion Incites Neuropsychiatric Symptoms of Systemic Lupus Erythematosus

Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE), including headaches, cognitive dysfunction and psychiatric disorders, appear in over half of SLE patients and may be among the earliest signs of SLE. However, these relatively non-specific symptoms make the diagnosis/treatment of NP-SLE problematic. Mice with an underlying defect in Fas (MRL/lpr) display cognitive and affective dysfunction characteristic of NP-SLE; however, this strain is one of only a few well-characterized murine models of NP-SLE, thus underscoring the paucity of tools available to uncover mechanisms contributing to NP-SLE. We have shown that mice with dendritic cell (DC)-specific loss of caspase-8 (CreCD11cCasp8flox/flox), an enzyme in the Fas pathway classically linked to apoptosis initiation and necroptosis suppression, develop an inflammatory disease reminiscent of both classic murine models of SLE and human SLE that originates from heightened DC activation. Strikingly, CreCD11cCasp8flox/flox mice also exhibit neurological deficits during the Morris water maze, contextual fear conditioning and rotarod tasks that indicate hippocampal and cerebellar abnormalities. Increased vascular permeability in CreCD11cCasp8flox/flox mice, as evidenced by Dynamic Intravascular Contrast Agent MRI, correlates with increased leukocyte infiltration seen by flow cytometric analysis. This infiltration resembles that of an acute model of traumatic brain injury, wherein physical damage to the brain promotes leakage of the blood-brain barrier. However, in our case, this breach is the direct result of DC-specific caspase-8 deletion and chronic systemic inflammation. These data substantiate a novel DC-specific mechanism whereby caspase-8 controls DC activation to prevent not only end-organ failure and peripheral pathology associated with SLE-like disease, but also NP-SLE manifestations, thus highlighting the use of this model to unlock underlying molecular mechanisms of disease.